Abstract: Mechanotransduction is the process by which mechanical energy is converted into electrical or biochemical signals. In mammals, mechanotransduction underlies a variety of senses, including hearing, touch and proprioception. Basic physiological processes, such as blood-pressure regulation and bladder function, also rely on mechanotransduction for normal homeostatic function. Despite its widespread importance, little is known about the molecular mechanisms underlying mechanotransduction in mammals. Do different cells use the same transduction molecules that are modified by cellular context? Or, are there multiple mechanotransducers that specialize in sensing different types of mechanical stimuli? The goal of his proposal is to identify molecules that mediate mechanotransduction in mammalian somatosensory neurons, the cells that convey our sense of touch and pain. While some candidate mechanotransducers have been identified, heterologous expression of these candidates has not yielded functional mechanosensitive channels, nor have gene knockout studies confirmed a role for any of these candidates in mammalian somatosensory mechanotransduction. My laboratory will undertake several unbiased approaches to identify new candidate mechanotransduction molecules. The specific aims of this proposal are to: (1) Identify components of the mechanotransduction machinery and (2) Examine the contribution of candidate molecules to somatosensation in vivo. These studies will provide novel insight into the molecular force transducers that underlie mammalian mechanotransduction. Public Health Relevance: Though unpleasant, pain warns us against harmful stimuli in the environment and evokes protective reflexes. But pain can also be a chronic, debilitating affliction that no longer serves a protective purpose. Chronic pain not only occurs after trauma-induced inflammation and tissue injury, but also results from many diseases;pain is the major complaint of patients suffering from cancer, AIDS, and diabetes. Understanding the mechanisms that evoke acute and chronic pain may lead to the development of much needed, new drugs and therapies to alleviate pain.